No overall increased risk of death in individuals with sickle cell trait: a study of 467 779 general population adults

ABSTRACT: Uncertainty remains about whether sickle cell trait (SCT) shortens life or predisposes to disease. Therefore, we examined whether SCT carriers had an increased risk of death or diseases linked to SCT. We studied 467 779 general population individuals from the UK Biobank. All had undergone whole-exome sequencing and were observed prospectively for a median of 15 years. Individuals with SCT (n = 1253) were not at an increased risk of all-cause death (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.84-1.29) or cardiovascular death (1.34; 0.90-2.00) or for having myocardial infarction (0.72; 0.42-1.24), ischemic stroke (1.30; 0.88-1.94), pulmonary embolism (1.29; 0.84-1.99), or heart failure (0.79; 0.55-1.14) compared with noncarriers. However, SCT carriers had an increased risk of diabetes (HR, 1.30; 95% CI, 1.12-1.50), chronic kidney disease (HR, 1.46; 95% CI, 1.18-1.80), and hypertension (odds ratio, 1.24; 95% CI, 1.08-1.42). Surprisingly, the risk of cardiovascular death was increased in SCT carriers with diabetes when compared with noncarriers with diabetes (HR, 2.17; 95% CI, 1.14-4.12). To examine whether selection bias may explain why previous studies based on hospital-diagnosed SCT found an increased risk of cardiovascular disease, we repeated our analyses using hospital diagnoses of SCT from national registries, instead of defining SCT from genotyping. Individuals registered as SCT carriers in hospital registries had a markedly increased risk of all-cause death (HR, 2.24; 95% CI, 1.42-3.52) and ischemic stroke (2.92; 1.30-6.60), likely due to selection bias. In conclusion, SCT carriers were not at an increased risk of all-cause death or cardiovascular disease.